Problems in the Bioinorganic Chemistry of Molybdenum and Tungsten

无机化学、生物无机化学和金属有机化学项目的这一奖项支持哈佛大学理查德·H·霍尔姆教授的研究，该研究集中在钼和钨氧转移酶和羟基酶催化的转化上。其中许多反应是纯氧原子(Oxo)转移过程，其中一个氧原子被插入或移除(oxo转移酶)，而另一些反应在催化反应中利用金属配位的氢氧化物(羟基酶)。这种含钨的酶通常存在于嗜热细菌和古生菌中。在几乎所有的情况下，氧原子的最终源或汇都是水。催化中心含有与一个或两个吡喃并二硫杂环戊烯配体结合的单核钼或钨原子。实验方法包括合成酶催化部位的低分子量类似物，并将其用于反应活性研究。这项研究建立在含有两个吡喃并二硫烯配体的酶的催化中心的合成和反应结果的类似物的基础上，并通过原子转移还原有机S氧化物和N-氧化物。天然配体由合成的二硫杂环戊烯代表，当它与钼或钨结合时，它的功能是烯-1，2-二硫代，并紧密地模拟了天然配位产生的电子环境。提出了一种新的、可能是通用的合成二硫茂络合物的方法，以考察硒还原酶、亚砷酸盐氧化酶、甲酸脱氢酶、乙炔水合酶、乙醛氧化酶和一氧化碳脱氢酶的类似反应。其他系统包括转羟基酶和乙苯脱氢酶。功能类似物系统与酶一样转化底物(但不一定在相同的反应速率域中)，金属位置与酶的金属位置可信地相似，并提供接近酶位置几何结构和电子结构的方法，是本研究的重点。钼和钨的酶参与了碳、氮、硫、砷和硒的全球循环。某些酶，如亚硫酸盐和黄嘌呤氧化酶，存在于人类体内；它们的故障会导致重大的健康风险。例如，亚硫酸盐氧化酶的缺乏可能会导致智力低下。生物合成吡喃并二硫杂环戊烯配体的能力降低将导致所有钼酶的缺陷，并伴随包括神经综合征在内的疾病。拟议研究的更广泛的潜在影响来自于更好地了解各级生物钼/钨中心的结构、功能和机制，并将这些信息纳入对这些元素和酶底物中所含元素的地球化学和环境循环的更好解释中。

This award in the Inorganic, Bioinorganic and Organometallic Chemistry program supports research by Professor Richard H. Holm at Harvard University that centers on transformations catalyzed by the molybdenum and tungsten oxotransferases and hydroxylases. Many of these reactions are pure oxygen atom (oxo) transfer processes, in which an oxygen atom is inserted or removed (oxotransferases) while others utilize metalcoordinated hydroxide in the catalytic reaction (hydroxylases). The tungsten-containing enzymes are usually found in hyperthermophilic bacteria and archaea. In practically all cases, the ultimate source or sink of oxygen atoms is water. The catalytic centers contain mononuclear molybdenum or tungsten atoms bound to one or two pyranopterindithiolene ligands. The experimental approach involves the synthesis of low molecular weight analogues of the catalytic sites of enzymes and their utilization in reactivity investigations. The research builds upon synthetic and reactivity results with analogues of the catalytic sites of enzymes that contain two pyranopterindithiolene ligands and reduce organic S-oxides and N-oxides by atom transfer. The natural ligand is represented by a synthetic dithiolene, which functions as an ene-1,2-dithiolate when bound to molybdenum or tungsten and closely simulates the electronic environment engendered by the native coordination. A new and possibly general method of synthesis of dithiolene complexes is proposed in order to examine analogue reactions of the enzymes selenate reductase, arsenite oxidase, formate dehydrogenase, acetylene hydratase, aldehyde oxidase, and carbon monoxide dehydrogenase. Other systems include the transhydroxylases and ethylbenzene dehydrogenase. Functional analogue systems that transform substrates as do enzymes (but not necessarily in the same reaction rate domain) with metal sites credibly similar to those of the enzymes and providing close approaches to enzyme-site geometric and electronic structures, are the focus of this research. Molybdenum and tungsten enzymes are implicated in global cycles thet process carbon, nitrogen, sulfur, arsenic, and selenium. Certain enzymes such as the sulfite and xanthine oxidases occur in humans; their malfunction leads to significant health risks. For example, the absence of sulfite oxidase can lead to mental retardation. Reduced ability to biosynthesize the pyranopterindithiolene ligand will lead to deficiencies in all molybdoenzymes with accompanying diseases including neurological syndromes. The broader potential impact of the proposed research derives from a better understanding of the structure, function, and mechanism of biological molybdenum/tungsten centers at all levels, and an integration of that information into improved interpretation of geochemical and environmental cycles of the these elements and those contained in enzymatic substrates.